1. Field of the Invention
The present invention concerns methods for decreasing the frequency of transmission of viral infection, such as human immunodeficiency virus and herpesvirus, and for preventing and treating sexually transmitted bacterial infections, such as Chlamydia trachomatis, by administration of cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate, which were heretofore employed as pharmaceutical excipients.
2. Background Information
a. Pharmaceutical Excipients
Pharmaceutical excipients are defined as inert substances that form a vehicle for drug delivery (Webster's Ninth New Collegiate Dictionary, Merriam-Webster Inc. Publishers, Springfield, Mass., USA, 1985, p. 432). Thus, excipients convert pharmacologically active compounds into pharmaceutical dosage forms suitable for administration to patients. Some excipients are also used for the formulation or production of confectionery, cosmetics and food products. Therefore, approved excipients are used frequently and at higher dosage levels in comparison with most drugs. Excipients are also much less expensive and more easily produced in very large scale in comparison with most drugs.
b. Sexually Transmitted Diseases ("STDs"): An Overview
The human immunodeficiency virus (HIV) pandemic is sustained and progressing predominantly due to sexual transmission of the virus (Mann, J.. M., Tarantola, D. J. M., Netter, T. W., "AIDS in the World", Cambridge: Harvard University Press, (1992)), facilitated by prior infection with other STD pathogens (Perine, P. L., "Sexually Transmitted Diseases in the Tropics", Med. J. Aust., 160, (1994), 358-366).
The urgent need to prevent the transmission of STDs has become highlighted by the HIV/AIDS epidemic, resulting so far in infection of approximately 42 million people and in approximately 12 million deaths (UNAIDS and WHO, Report on the global HIV/AIDS epidemic, Geneva: Joint United Nations Programme on HIV/AIDS, Jun. 1, 1998). The facts that HIV infections are not curable as of now, have become the leading cause of death among young adults and has decreased life expectancy in a number of countries, and the observation that several non-viral STDs facilitate HIV infection, have further emphasized the pressing need for new preventive approaches.
Treatment of STDs (other than HIV) was found to be a feasible and economically justifiable approach to decreasing the rate of HIV-1 transmission (St. Louis, M. E., Levine, W. C., Wasserheit, J. N. et al, "HIV Prevention Through Early Detection and Treatment of Other Sexually Transmitted Diseases--United States Recommendation of the Advisory Committee for HIV and STD Prevention", Mor. Mort. Wkly. Rep., (1998), 47 (No. RR-12), 1-24; Over, M., Piot, P., "Human Immunodeficiency Virus Infection and Other Sexually Transmitted Diseases in Developing Countries: Public Health Importance and Priorities for Resource Allocation", J. Infect. Dis., (1996), 174 (Suppl. 2), 162-175). However, this beneficial approach is not sufficient to control the spread of STDs, including HIV-1.
In the absence of prophylactic vaccines against STD pathogens and HIV in the foreseeable future, and of safe anti-HIV-1 drugs affordable in developing countries, other simple methods to control the sexual transmission of STDs, including HIV-1, must be applied. This includes mechanical (condom) and chemical barrier methods and combinations thereof. Formulations of spermicides shown in vitro to inactivate STD pathogens have been considered for this purpose, but based on the outcome of clinical safety and efficacy trials, their utility remains in doubt.
The use of chemical barrier methods (topical "microbicides") under the control of women has been proposed as a method to control the sexual transmission of HIV-1 and other STDs (Alexander, N. J., "Barriers to Sexually Transmitted Diseases", Scientific American & Medicine, (1996), 3:32-41). The fastest way to introduce topical microbicides into practice appeared to be the application of over-the-counter (OTC) contraceptives containing the detergent nonoxynol-9 (N-9). N-9 was shown to inactivate in vitro HIV-1 (Hicks, D. R., Martin, L. S., Getchell, J. P. et al., "Inactivation of HTLV-III/LAV-infected Cultures of Normal Human Lymphocytes by Nonoxynol-9 in vitro", Lancet, (1985), 2:1422-1423; Jennings, R., Clegg, A., "The Inhibitory Effect of Spermicidal Agents on Replication of HSV-2 and HIV-1 in vitro", J. Antimicrob. Chemother., (1993), 32:71-82), HSV-2 (Sugarman, B., Mummaw, N., "Effects of Antimicrobial Agents on Growth and Chemotaxis of Trichomonas Vaginalis", Antimicrob. Agents Chemother., (1988), 32:1323-1326) and Chlamydia trachomatis (Lyons, J. M., Ito, J. I., Jr., "Reducing the Risk of Chlamydia Trachomatis Genital Tract Infection by Evaluating The Prophylactic Potential of Vaginally Applied Chemicals", Clin. Infect. Dis., (1995), 21 (Suppl. 2): S174-S177). N-9 was also found to be cytotoxic. This approach seems to be hampered by clinical data suggesting the adverse effects of some N-9 formulations (Stafford, M. K., Ward, H., Flanagan, A., et al., "Safety Study of Nonoxynol-9 As A Vaginal Microbicide: Evidence of Adverse Effects", J. Acquir. Imm. Defic. Synd. Hum. Retrovir., (1998), 17:327-331; Rosenstein, I. J., Stafford, M. K., Kitchen, V. S. et al., "Effects on Normal Vaginal Flora of Three Intravaginal Microbicidal Agents Potentially Active Against Human Immunodeficiency Virus Type 1", J. Infect. Dis., (1998), 177:1386-1390; Kilmarx, P. H., Limpakarnjanarat, K., Supawitkul, S. et al., "Mucosal Disruption Due To Use of A Widely-distributed Commercial Vaginal Product: Potential to Facilitate HIV Transmission", AIDS, (1998), 12:767-773) and lack of efficacy in decreasing the rate of heterosexual HIV-1, gonorrhea and chlamydia transmission by one of the N-9 formulations (Roddy, R. E., Zekeng, L., Ryan, K. A. et al., "A Controlled Trial of Nonoxynol 9 Film to Reduce Male-to-Female Transmission of Sexually Transmitted Diseases", N. Engl. J. Med., (1998), 339, 504-510). This indicates that other microbicidal compounds have to be tested as prophylactic agents against HIV-1 and other STDs.
Considering the urgency in controlling the HIV epidemic, the rapid development of other microbiocidal formulations is needed. The introduction of such microbicide formulations into practice would be significantly enhanced by using active ingredients with an already establshed safety record for human use.
To search for safe microbicide formulations, criteria distinct from those applied to screening for anti-HIV-1 drugs have to be used, raising the possibility that promising microbicides with anti-HIV-1 activity may heretofore have been missed during extensive screening for therapeutic anti-HIV-1 compounds. The criteria for selection of anti-HIV-1 microbicides, as compared with those for therapeutic anti-HIV drugs, can be summarized as follows: (a) undesirability of systemic spread leading to preferred consideration of high molecular weight compounds (M.sub.w .gtoreq.2 kD), which are active selectively at the site of application; (b) high degree of safety and lack of side effects (due to repeated use by healthy people -as compared with the use of therapeutic anti-HIV-1 drugs by already infected individuals), the safety being augmented by the lack of systemic spread; (c) consideration of compounds with lower specific antiviral activity, which can be compensated for by higher concentrations of the compounds with established safety, and (d) activity directed to early steps in injection and, preferably, direct pathogen inactivation, as implied by the term "microbicide".
Compounds meeting at least some of these criteria are as follows: (a) sulfated polysaccharides (Javan, C. M., Gooderham, N. J., Edwards, R. J. et al., "Anti-HIV Type 1 Activity of Sulfated Derivatives of Dextrin Against Primary Viral Isolates of HIV Type 1 in Lymphocytes and Monocyte-Derived Macrophages", AIDS Res. Human Retroviruses, (1997), 13, 875-880; Stafford, M. K., Cain, D., Rosenstein, I., et al., "A Placebo-Controlled, Double Blind Prospective Study in Healthy Female Volunteers of Dextrin Sulphate Gel: A Novel Potential Intravaginal Virucide", J. Acquir. Immune Defic. Syndr. Hum. Retrovirol., (1997), 14, 213-218; Zacharopoulos, V. R., Phillips, D. M., "Vaginal Formulations of Carrageenan Protect Mice From Herpes Simplex Virus Infection", Clin. Diagn. Lab. Immunol., (1997), 4, 465-468; Carlucci, M. J., Pujol, C. A., Ciancia, M. et al., "Antiherpetic and Anticoagulant Properties of Carrageenans From the Red Seaweed Gigartina Skottsbergii and Their Cyclized Derivatives: Correlation Between Structure and Biological Activity", Int. J. Biol. Macromol., (1997), 20, 97-105) and other sulfonated polymers (however, the virucidal and bacterial activity of these compounds has not been established and their activity is ascribed to their ability to interact with target cells to inhibit virus entry (Rusconi, S., Moonis, M., Merill, D. P. et al., "Naphthalene Sulfonate Polymers With CD-4-Blocking and Anti-Human Immunodeficiency Virus Type 1 Activities", Anticrob. Agents Chemother., (1996), 40, 234-236; McClure, M. O., Moore, J. P., Blanc, D. F. et al., "Investigations into the Mechanism By Which Sulfated Polysaccharides Inhibit HIV Infection In Vitro", AIDS Res. Hum. Retroviruses, (1992), 8, 19-26); and (b) protegrins which have broad spectrum activity against bacteria and enveloped viruses (Tamamura, H., Murakami, T., Horiuchi, S. et al., "Synthesis of Protegrin-Related Peptides and Their Antibacterial and Anti-Human Immunodeficiency Virus Activity", Chem. Pharm. Bull., (Tokyo), (1995), 43, 853-858; Lehrer, R. I., Ganz, T., "Endogenous Vertebrate Antibiotics, Defensins, Protegrins, and Other Cysteine-Rich Antimicrobial Peptides", Ann. N.Y., Acad. Sci., (1996), 797, 228-239; Qu, X. D., Harwig, S. S., Shafer, W. M. et al., "Protegrin Structure and Activity Against Neisseria Gonorrhoeae", Infect. Immun., (1997), 65, 636-639), but they also have undesirable activity against Lactobacilli and their application may have economical disadvantages, as compared with that of sulfated polymers.
Since efficacious topical "microbicides" would be expected to be used repeatedly over decades, they should have an established safety record and should preferably not be spread systemically after topical application. They should have the following characteristics: (a) be inexpensive, (b) be produced from widely available resources, (c) have a broad specificity resulting in prevention of transmission of several STDs, and (d) inactivate the infectivity of the respective STD pathogens. In accordance with these requirements, some of the present inventors recently developed a potent anti-HIV and anti-herpesvirus agent, suitable for incorporation into topical gels/creams (Neurath, A. R., Jiang, S., Strick, N. et al., "Bovine .beta.-Lactoglobulin Modified by 3-Hydroxyphthalic Anhydride Blocks the CD4 Cell Receptor for HIV", Nature Med., (1996), 2, 230-234; Neurath, A. R., Debnath, A. K., Strick, N. et al., "3-Hydroxyphthaloyl .beta.-Lactoglobulin, I, Optimization of Production and Comparison With Other Compounds Considered for Chemoprophylaxis of Mucosally Transmitted Human Immunodeficiency Virus Type 1", Antiviral Chem. Chemother., (1997), 8, 131-140; Neurath, A. R., Debnath, A. K. Strick N. et al., "3-Hydroxyphthaloyl .beta.-Lactoglobulin, II, Anti-Human Immunodeficiency Virus Type 1 Activity in in vitro Environments Relevant to Prevention of Sexual Transmission of the Virus", Antiviral Chem. Chemother., (1997), 8, 141-148; Neurath, A. R., Strick, N., Li, Y-Y, "3-Hydroxyphthaloyl .beta.-lactoglobulin, III. Antiviral Activity Against Herpesviruses", Antiviral Chem. Chemother., (1998), 9, 177-184; Kokuba, H., Aurelian, L., Neurath, A. R., "3-Hydroxyphthaloyl .beta.-Lactoglobulin, IV, Antiviral Activity in the Mouse Model of Genital Herpevirus Infection", Antiviral Chem. Chemother., (1998), 9, 353-357, by chemical modification of the bovine milk product .beta.-lactoglobulin with 3-hydroxyphthalic anhydride. Possible disadvantages of this antiviral compound has been the lack of activity against bacterial STD pathogens.
c. Viral Infections
Human immunodeficiency viruses ("HIV") have been known as the causative virus for AIDS (Acquired Immunodeficiency Syndrome). The prevalence of AIDS cases is presently increasing at an alarming rate.
Two related retroviruses that can cause AIDS are human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The genomes of these two viruses are about 50% homologous at the nucleotide level, contain the same complement of genes, and appear to attack and kill the same human cells by the same mechanism.
HIV-1 was identified in 1983. Virtually all AIDS cases in the United States are associated with HIV-1 infection. HIV-2 was isolated in 1986 from West African AIDS patients.
HIV-1 and HIV-2 are retroviruses in which the genetic material is RNA, rather than DNA. The HIV-1 and HIV-2 viruses carry with them a polymerase (reverse transcriptase) that catalyzes transcription of viral RNA into double-helical DNA.
The viral DNA can exist as an unintegrated form in the infected cell or be integrated into the genome of the host cell. As presently understood, the HIV enters the T4 lymphocyte where it loses its outer envelope, releasing viral RNA and reverse transcriptase.
The reverse transcriptase catalyzes synthesis of a complementary DNA strand from the viral RNA template. The DNA helix then inserts into the host genome where it is known as the provirus. The integrated DNA may persist as a latent infection characterized by little or no production of virus or helper/inducer cell death for an indefinite period of time. When the viral DNA is transcribed and translated by the infected lymphocyte, new viral RNA and proteins are produced to form new viruses that bud from the cell membrane and infect other cells.
Attempts to treat AIDS with drugs which inhibit reverse transcriptase such as 3'-azido-3'-deoxythymidine (AZT) have not been met with a desirable degree of success. Moreover, there is a potential for toxicity with the use of anti-viral drugs. Thus there is a need for an effective and safe means to prevent and treat AIDS.
HIV infections are transmitted by means such as contaminated intravenous drug needles and through sexual contact. Sexual transmission is the most frequent (86%) route of adult HIV-1 infections worldwide (AIDS in the World, Harvard University Press, Cambridge, Mass., (1992)).
The transmission of HIV by heterosexual sex poses an especially severe problem for women. By the year 2,000, it is estimated that 90% of HIV infections will be acquired via heterosexual intercourse.
The utilization of condoms provides a substantial degree of protection against transmission of HIV and herpesvirus infections during sexual intercourse, but a difficulty arises when condoms are not employed. Moreover, the use of condoms appears to be a culturally and socially unacceptable practice in many countries.
Although men can protect themselves from sexually transmitted HIV and herpesvirus infection by using condoms, women who are sexually active have no similar means. Women can encourage their male sex partners to use a condom, but may not succeed. The female condom, which is just becoming available, is expensive and there is presently no evidence that it prevents sexual transmission of HIV or herpesvirus.
Even maintaining a monogamous sexual relationship is no guarantee of safety, for if a woman's male partner becomes infected, he can pass the virus to her. And as more women are infected, so are more babies.
There is presently frustration in the medical field by the bleak prospect for an effective AIDS vaccine in the near future and the severe limitations of drugs that effectively and safely combat HIV.
Due to the present absence of a prophylactic anti-HIV vaccine and because of limitations of educational programs, other preventive methods have been sought. Spermicides with virucidal properties have been considered for this purpose, but their application is contraindicated by adverse effects (Bird, K. D., "The Use of Spermicide Containing Nonoxynol-9 in the Prevention of HIV Infection", AIDS, 5, 791-796 (1991)).
Anti-HIV drugs currently in use or expected to be clinically applied in the near future (Steele, F., "AIDS Drugs Lurch Towards Market", Nature Medicine, 1, 285-286 (1995)) are mostly not targeted to the earliest steps in the virus replicative cycle, lead to the emergence of drug resistant mutants, and are expensive, suggesting that their application for wide use in topical chemoprophylaxis is unlikely.
Cells which are the primary targets for sexual and mucosal transmission of HIV, either in the form of free virus or virus-infected cells, have not been fully defined and may be diverse (Miller, C. J. et al., "Genital Mucosal Transmission of Simian Immunodeficiency Virus: Animal Model for Heterosexual Transmission of Human Immunodeficiency Virus", J. Virol., 63, 4277-4284 (1989); Phillips, D. M. and Bourinbaiar, A. S., "Mechanism of HIV Spread from Lymphocytes to Epithelia", Virology, 186, 261-273 (1992); Phillips, D. M., Tan, X., Pearce-Pratt, R. and Zacharopoulos, V. R., "An Assay for HIV Infection of Cultured Human Cervix-derived Cells", J. Virol. Methods, 52, 1-13 (1995); Ho, J. L. et al., "Neutrophils from Human Immunodeficiency Virus (HIV)-Seronegative Donors Induce HIV Replication from HIV-infected Patients Mononuclear Cells and Cell lines": An In Vitro Model of HIV Transmission Facilitated by Chlamydia Trachomatis.," J. Exp. Med., 181, 1493-1505 (1995); and Braathen, L. R. & Mork, C. in "HIV infection of Skin Langerhans Cells", In: Skin Langerhans (dendritic) cells in virus infections and AIDS (ed. Becker, Y.) 131-139 (Kluwer Academic Publishers, Boston, (1991)). Such cells include T lymphocytes, monocytes/macrophages and dendritic cells, suggesting that CD4 cell receptors are engaged in the process of virus transmission (Parr, M. B. and Parr, E. L., "Langerhans Cells and T lymphocyte Subsets in the Murine Vagina and Cervix", Biology of Reproduction, 44, 491-498 (1991); Pope, M. et al., "Conjugates of Dendritic Cells and Memory T Lymphocytes from Skin Facilitate Productive Infection With HIV-1", Cell, 78, 389-398 (1994); and Wira, C. R. and Rossoll, R. M., "Antigen-presenting Cells in the Female Reproductive Tract: Influence of Sex Hormones on Antigen Presentation in the Vagina", Immunology, 84, 505-508 (1995)).
Therefore agents blocking HIV-CD4 binding are expected to diminish or prevent virus transmission. Soluble recombinant CD4 cannot be considered for this purpose since high concentrations are required to neutralize the infectivity of primary HIV isolates (Daar, E. S., Li, X. L., Moudgil, T. and Ho, D. D., "High Concentrations of Recombinant Soluble CD4 are Required to Neutralize Primary Human Immunodeficiency Virus Type 1 Isolates", Proc. Natl. Acad. Sci. U.S.A., 87, 6574-6578 (1990), and in the case of SIV, the infectivity is enhanced by CD4 (Werner, A., Winskowsky, G. and Kurth, R., "Soluble CD4 Enhances Simian Immunodeficiency Virus SIVagm Infection", J. Virol., 64, 6252-6256 (1990)). However, anti-CD4 antibodies are expected to prevent virus transmission independently of subtype and variability, but their application would be too costly (Daar et al, supra, Watanabe, M., Boyson, J. E., Lord, C. I. and Letvin, N. L. "Chimpanzees Immunized with Recombinant Soluble CD4 Develop Anti-self CD4 Antibody Responses with Anti-human Immunodeficiency Virus Activity", Proc. Natl. Acad. Sci. U.S.A., 89, 5103-5107 (1992); and Perno, C.-F., Baseler, M. W., Broder, S. and Yarchoan, R., "Infection of Monocytes by Human Immunodeficiency Virus Type 1 Blocked by Inhibitors of CD4-gp120 Binding, Even in the Presence of Enhancing Antibodies", J. Exp. Med., 171, 1043-1056 (1990)).
There is a need for a safe and effective substance that can be inserted into the vagina by a foam, gel, sponge or other form to prevent HIV-1 or HIV-2 from infecting cells in the body. It is hoped that such substance be used by a woman without her partner's knowledge.
Prospects for the near and possibly not so near future to prevent HIV-1 transmission by vaccination do not seem good. A recent report that vaccination with inactivated SIV did not protect African Green monkeys against infection with the homologous virus notwithstanding a strong immune response to SIV does not appear to be encouraging in this respect (Siegel, F., Kurth, R., and Norley, S., (1995), "Neither Whole Inactivated Virus Immunogen nor Passive Immunoglobulin Transfer Protects Against SIV.sub.agm Infection in the African Green Monkey Natural Host", J. AIDS, 8, 217-226). Considering this problem, emphasis has been put on attempts to build a chemical barrier to HIV-1 transmission (Taylor, (1994), "Building a Chemical Barrier to HIV-1 Transmission", J. NIH Res., 6, 26-27).
The development of topically applied microbicides, expected to prevent sexual (mucosal) transmission of HIV-1, was suggested to need to be "effective against all sexually transmitted diseases and should not be seen, smelled, or felt while in use." It should also be inexpensive and widely available, and $25 million was expected to be devoted to its development in the United States in 1995 (Taylor, (1994) supra). Detergents (nonoxynol-9) as a universal pathogen killer have been selected for clinical trials. However, not surprisingly, this compound proved to be deleterious to the host.
Targeting the chemical barrier to transmission of individual pathogens could perhaps facilitate the development of compounds preventing the transmission of human immunodeficiency viruses. For example, effective blockade of receptors for the viruses might accomplish this goal. This concept may be supported by the finding that immunization of chimpanzees and rhesus monkeys, respectively, with human CD4 which has several amino acid point mutations in comparison with non-human primate CD4 sequences (Fomsgaard, A., Hirsch, V. M., and Johnson, P. R., (1992), "Cloning and Sequences of Primate CD4 molecules: Diversity of the Cellular Receptor for Simian Immunodeficiency Virus/Human Immunodeficiency Virus", Eur. J. Immunol., 22, 2973-2981), developed anti-CD4 antibodies which inhibited HIV-1 and SIV replication (Watanabe, M., Levine, C. G., Shen, L., Fisher, R. A., and Letvin, N. L. (1991), "Immunization of Simian Immunodeficiency Virus-Infected Rhesus Monkeys with Soluble Human CD4 Elicits an Antiviral Response," Proc. Natl. Acad. Sci. USA, 88, 4616-4620. Watanabe, M., Chen, Z. W., Tsubota, H., Lord, C. I., Levine, C. G., and Letvin, N. L., (1991), "Soluble Human CD4 Elicits an Antibody Response in Rhesus Monkeys that Inhibits Simian Immunodeficiency Virus Replication", Proc. Natl. Acad. Sci. USA, 88, 120-124; and Watanabe, M., Boyson, J. E., Lord, C. I., and Letvin, N. L., (1992), "Chimpanzees Immunized with Recombinant Soluble CD4 Develop Anti-self CD4 Antibody Responses with Anti-human Immunodeficiency Virus Activity", Proc. Natl. Acad. Sci. USA, 89, 5103-5107).
Herpesviruses include the following viruses isolated from humans:
(1) herpes simplex virus 1 ("HSV-1") PA0 (2) herpes simplex virus 2 ("HSV-2") PA0 (3) human cytomegalovirus ("HCMV") PA0 (4) varicella-zoster virus ("VZV") PA0 (5) Epstein-Barr virus ("EBV") PA0 (6) human herpesvirus 6 ("HHV6") PA0 (7) herpes simplex virus 7 ("HSV-7") PA0 (8) herpes simplex virus 8 ("HSV-8")
Herpesviruses have also been isolated from horses, cattle, pigs (pseudorabies virus ("PSV") and porcine cytomegalovirus), chickens (infectious larygotracheitis), chimpanzees, birds (Marck's disease herpesvirus 1 and 2), turkeys and fish (see "Herpesviridae: A Brief Introduction", Virology, Second Edition, edited by B. N. Fields, Chapter 64, 1787 (1990)).
Herpes simplex viral ("HSV") infection is generally a recurrent viral infection characterized by the appearance on the skin or mucous membranes of single or multiple clusters of small vesicles, filled with clear fluid, on slightly raised inflammatory bases.
The herpes simplex virus is a relatively large-sized virus. HSV-2 commonly causes herpes labialis. HSV-2 is usually, though not always, recoverable from genital lesions. Ordinarily, HSV-2 is transmitted venereally.
At least 20% of people in the United States have been infected with herpesvirus type 2 (HSV-2), which is usually transmitted sexually and can cause recurrent genital ulcers (Fleming, D. T., McQuillan, G. M., Johnson, R. E. et al., "Herpes simplex virus type 2 in the United States, 1976 to 1994", N. Eng. J. Med., (1997), 337:1105-1111; Arvin, A. M., Prober, C. G., "Herpes Simplex Virus Type 2--A Persistent Problem", N. Engl. J. Med., (1997), 337:1158-1159). The prevalence of HSV-2 infections is even higher in some developing countries (Nahmias, A. J., Lee, F. K., Beckman-Nahmias, S., "Sero-epidemiologial and Sociological Patterns of Herpes Simplex Virus Infection in the World", Scand. J. Infect. Dis., (1990), Suppl. 69:19-36). Although the infection is treatable by antiviral drugs, efficacious long-term suppression of genital herpes is expensive (Engel, J. P., "Long-term Suppression of Genital Herpes", JAMA, (1998), 280:928-929). The probability of further spread of the virus by untreated people and asymptomatic carriers not receiving antiviral therapy is extremely high, considering the high prevalence of infections. Other herpesviruses, including cytomegalovirus (Krieger, J. N., Coombs, R. W., Collier, A. C. et al., "Seminal Shedding of Human Immunodeficiency Virus Type 1 and Human Cytomegalovirus: Evidence For Different Immunologic Controls", J. Infect. Dis., (1995), 171:1018-1022; van der Meer, J. T. M., Drew, W. L., Bowden R. A. et al., "Summary of the International Consensus Symposium on Advances in the Diagnosis, Treatment and Prophylaxis of Cytomegalovirus Infection", Antiviral Res., (1996), 32:119-140) (HCMV), herpesvirus 6 (Leach, C. T., Newton, E. R., McParlin, S. et al., "Human Herpesvirus 6 Infection of the Female Genital Tract", J. Infect. Dis., (1994), 169:1281-1283), and herpesvirus 8 (Howard, M. R., Whitby, D., Bahadur, G. et al., "Detection of Human Herpesvirus 8 DNA in Semen from HIV-infected Individuals But Not Healthy Semen Donors", AIDS, (1997), 11:F15-F19), the causative agent of Kaposi's sarcoma, are also transmitted sexually.
The time of initial herpes simplex virus infection is usually obscure except in the uncommon primary systemic infection occurring in infants and is characterized by generalized cutaneous and mucous membrane lesions accompanied by severe constitutional symptoms. Localized infections ordinarily appear in childhood, but may be delayed until adult life. It is presumed that the herpes simplex virus remains dormant in the skin and that herpetic eruptions are precipitated by overexposure to sunlight, febrile illnesses, or physical or emotional stress; also, certain foods and drugs have been implicated. In many instances, the trigger mechanism remains undetected.
The lesions caused by herpes simplex virus may appear anywhere on the skin or on mucous membranes, but are most frequent on the face, especially around the mouth or on the lips, conjunctiva and cornea, or the genitals. The appearance of small tense vesicles on an erythematous base follows a short prodromal period of tingling discomfort or itching. Single clusters may vary from 0.5 to 1.5 cm in size, but several groups may coalesce. Herpes simplex on skin tensely attached to underlying structures (for example, the nose, ears or fingers) may be painful. The vesicles may persist for a few days, then begin to dry, forming a thin yellowish crust. Healing usually occurs within 10 days after onset. In moist body areas, healing may be slower, with secondary inflammation. Healing of individual herpetic lesions is usually complete, but recurrent lesions at the same site may result in atrophy and scarring.
In females infected with HSV-2, there may be no skin lesions, the infection may remain entirely within the vagina. The cervix is frequently involved, and there is increasing evidence that this may be a factor in the development of carcinoma of the cervix.
Corneal lesions commonly consist of a recurrent herpetic keratitis, manifest by an irregular dendritic ulcer on the superficial layers. Scarring and subsequent impairment of vision may follow.
Gingivostomatitis and vulvovaginitis may occur as a result of herpes infection in infants or young children. Symptoms include irritability, anorexia, fever, inflammation, and whitish plaques and ulcers of the mouth. Particularly in infants, though sometimes in older children, primary infections may cause extensive organ involvement and fatal viremia.
In women who have an attack of HSV-2 late in pregnancy, the infection may be transmitted to the fetus, with the development of severe viremia. Herpes simplex virus may also produce fatal encephalitis.
Kaposi's varicelliform eruption (eczema herpeticum) is a potentially fatal complication of infantile or adult atopic eczema. Exposure of patients with extensive atopic dermatitis to persons with active herpes simplex should be avoided.
No local or systemic chemotherapeutic agent has been demonstrated to be effective for treating herpes simplex virus with the possible exception of topical idoxuridine (IDU) in superficial herpetic keratitis. Reports on this compound in cutaneous herpes are conflicting. Other drugs which have been employed to treat HSV include trifluorothymidine, vidarabine (adenine arabinoside, ara-A), acyclovir, and other inhibitors of viral DNA synthesis may be effective in herpetic keratitis. These drugs inhibit herpes simplex virus replication and may suppress clinical manifestations. However, the herpes simplex virus remains latent in the sensory ganglia, and the rate of relapse is similar in drug-treated and untreated individuals. Moreover, some drug-resistant herpes virus strains have emerged.
Diseases caused by varicella-zoster virus (human herpesvirus 3) include varicella (chickenpox) and zoster (shingles).
Cytomegalovirus (human herpesvirus 5) is responsible for cytomegalic inclusion disease in infants. There is presently no specific treatment for treating patients infected with cytomegalovirus.
Epstein-Barr virus (human herpesvirus 4) is the causative agent of infectious mononucleosis and has been associated with Burkitt's lymphoma and nasopharyngeal carcinoma.
Animal herpesviruses which may pose a problem for humans include B virus (herpesvirus of Old World Monkeys) and Marmoset herpesvirus (herpesvirus of New World Monkeys).
In searching for inexpensive antiviral compounds which could be applied topically to decrease the frequency of sexual transmission of the human immunodeficiency virus type 1 (HIV-1) and herpesviruses (HSV), applicants decided against all odds to screen excipients for anti-HIV-1 activity and discovered the present invention which involves the administration of cellulose acetate phthalate ("CAP") or hydroxypropyl methylcellulose phthalate ("HPMCP").
d. Sexually Transmitted Diseases of Bacterial Origin
Curable sexually transmitted diseases (STDs) of bacterial origin are the most common worldwide cause of illness with significant health, social and economic consequences. They can lead to long-term, serious complications and sequelae. The estimated annual (1995) worldwide incidence of four major curable STDs, namely syphillis, gonorrhea (Neisseria gonorrhoeae), chlamydia and trichomoniasis, was about 330 million (Gerbase, A. C., Rowley, J. T., Heymann, D. H. L. et al., "Global Prevalence and Incidence Estimates of Selected Curable STDs", Sex. Transm. Inf., (1998), 74 (Suppl. 1): S12-S16). Another treatable STD, chancroid, a genital ulcerative disease caused by Haemophilus ducreyi, is common in developing countries in Africa, Asia and Latin America, where incidence may exceed that of syphillis (Trees, D. L., Morse, S. A., "Chancroid and Haemophilus ducreyi: An Update", Clin. Microb. Rev., (1995), 8:357-375). The proposed control measures for these STDs include the following: surveillance, laboratory diagnosis, syndromic management, data monitoring, treatment with antibacterial agents, partner notification and development of vaccines (Rao, P., Mohamedali, F. Y., Temmerman, M. et al., "Systematic Analysis of STD Control: an Operational Model", Sex. Transm. Inf., (1998), 74 (Suppl 1): S17-S22; Dallabetta, G. A., Gerbase, A. C., Holmes, K. K., "Problems, Solutions, and Challenges in Syndromic Management of Sexually Transmitted Diseases", Sex. Transm. Inf., (1998), 74 (Suppl 1): S1-S11; Burstein, G. R., Gaydos, C. A., Diener-West M., "Incident Chlamydia Trachomatis Infections Among Inner-city Adolescent Females", JAMA, (1998), 280:521-526).
There has thus heretofore been desired the development of a topical microbicide from inexpensive, widely available resources, with broad antiviral and antibacterial activities.